Throughout this application various publications are referred to in parentheses. Full citations for these references may be found at the end of the specification. The disclosures of these publications, and all patents, patent application publications and books referred to herein, are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
Interactions between members of the B7 ligand and CD28 receptor families generate positive costimulation and negative coinhibition, which are of central importance in regulating T cell responses (1-3). B7-1/B7-2/CD28/CTLA-4 is the most extensively characterized of these pathways. Ligands B7-1 (CD80) and B7-2 (CD86) on antigen-presenting cells (APCs) bind to CD28 on naïve T cells, and provide a major costimulatory signal to activate naïve T cells. After the initial activation, coinhibitory molecule cytotoxic T lymphocyte antigen-4 (CTLA-4, CD152) is induced on T cells and engages the same B7-1 and B7-2 ligands in order to restrain T cell function. In contrast to the costimulatory activity of CD28, the interaction of B7-1 or B7-2 with CTLA-4 is essential for limiting the proliferative response of recently activated T cells to antigen and CD28-mediated costimulation.
During the past decade, several new pathways in the B7 and CD28 families have been identified, including B7h/ICOS, PD-L1/PD-L2/PD-1, B7-H3/receptor and B7x/receptor. B7h (4) (also called ICOS-L, B7RP-1(5), GL50(6), B7H2(7), LCOS(8), and CD275) binds to the inducible costimulator (ICOS, CD278) on activated T cells (9), which induces strong phosphatidylinositol 3-kinase activity (10, 11) and leads to the expression of transcription factors involved in follicular helper CD4 T (Tfh) differentiation (12). Therefore, the B7h/ICOS pathway provides critical T cell help to B cells. Deficiencies in this pathway result in substantially reduced numbers of memory B cells and markedly reduced levels of serum Ig in patients with common variable immunodeficiency (13). In humans, but not in mice, B7h can bind both CD28 and CTLA-4 (14). The B7 family members PD-L1 (15) (also termed B7-H1(16), CD274) and PD-L2 (17) (also called B7-DC(18), CD273) bind to the programmed death 1 receptor (PD-1, CD279), which ultimately decreases induction of cytokines and cell survival proteins in T cells. The PD-L/PD-1 pathway plays an important role in the control of tolerance and autoimmunity (19), and contributes critically to T cell exhaustion and viral persistence during chronic infections (20). In addition, PD-L1 can also bind to B7-1(21).
B7-H3 (22)(CD276) and B7x (23) (also called B7-H4 (24) or B7S1 (25)) are recently discovered members of the B7 family, and their contributions to immune response have not yet been clearly defined. B7-H3 binds activated T cells, but the physiological role of this pathway is unclear, as both costimulatory and coinhibitory effects have been observed (26). B7x binds activated T cells and inhibits T cell functions. In addition, myeloid derived suppressor cells (MDSCs) also express a receptor for B7x (27). Clinical data also support a coinhibitory function for B7x, as aberrant expression of this molecule is observed in many types of human cancers and is often associated with enhanced disease progression and poor clinical outcome (28). It appears that the B7x pathway is exploited as part of the immune evasion mechanisms used by many human cancers. Collectively, the regulated spatial and temporal expression of costimulatory and coinhibitory B7 molecules provides the controls that underlie T cell-mediated immune responses.
Due to their fundamental biological importance and therapeutic potential, there has been considerable interest in the identification of additional molecules with costimulatory or coinhibitory function.
The present invention addresses the need for improved therapies and therapeutics based on a novel B7/CD28 family pathway, namely, a HERV-H LTR Associating Protein 2 (HHLA2) pathway.